Mechanistically, Ang II upregulated β5i expression to promote ATRAP degradation, which resulted in activation of AT1R-mediated NF-κB signaling, increased NADPH oxidase activity, increased TGF (transforming growth factor)-β1/Smad signaling, and altered the expression of Kir2.1 and CX43 (connexin 43) in the atria, thereby affecting atrial remodeling and AF.
In wild-type mice, Ang II increased susceptibility to AF in association with a prolongation of P-wave duration, increased atrial refractory period, and slowed atrial conduction.
Electrophysiological study was conducted to demonstrate the effect of KCNQ1OT1 and CACNA1C on the Effective refractory period (ERP), interatrial conduction time (IACT), incidence of AF and AF duration of Ang-II-induced mice heart.
After angiotensin-II (Ang-II) stimulation which mimicked atrial fibrosis progression, ALK4-deficient mice showed lower expression of ALK4 in atriums, reduced activation of atrial fibroblasts, blunted atrial enlargement and atrial fibrosis, and further reduced AF vulnerability upon right atrial electrophysiological studies as compared to wild-type littermates.